Skip to main content
SpringerLink
Log in

Novel Views on Heart Function from Dynamic Hyperpolarized NMR

  • Chapter
  • First Online:
Dynamic Hyperpolarized Nuclear Magnetic Resonance

Part of the book series: Handbook of Modern Biophysics ((HBBT))

  • 464 Accesses

Abstract

The heart beats constantly and requires continuous production of adenosine triphosphate (ATP) to power contraction. ATP is generated predominantly in the mitochondria, from fuels such as fatty acids and glucose. Many cardiac pathologies, such as heart failure, hypertrophy and diabetic cardiomyopathy, are associated with changes in cardiac metabolism. Historically, however, metabolic fluxes have been impossible to assess in vivo in real time. Hyperpolarized magnetic resonance imaging (MRI), by the process of dynamic nuclear polarization of 13C-labeled metabolic probes, has revolutionized metabolic imaging in vivo over the last 15 years. The most commonly used metabolic probe is [1-13C]pyruvate, which can provide information on anaerobic glycolysis through carbon-13 label exchange into the endogenous lactate pool as well as oxidative carbohydrate metabolism through 13C-labelling of bicarbonate, the by-product of the pyruvate dehydrogenase complex. This chapter introduces normal cardiac metabolism and then highlights the challenges and methods used for cardiac metabolic imaging. Next, key studies showing physiological metabolism in the isolated perfused heart, in rodents, and in large animals are summarized. Non-metabolic imaging techniques that can use hyperpolarized 13C-labelled probes to assess perfusion, pHi and cellular redox state are described. Finally, key studies undertaken in animal models of cardiac pathologies are described to highlight the potential for emerging human studies performed using hyperpolarized MRI.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ingwall: ATP and the heart. Kluwer Academic, Boston (2002)

    Book  Google Scholar 

  2. Lopaschuk, G.D., Ussher, J.R., Folmes, C.D.L., Jaswal, J.S., Stanley, W.C.: Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90, 207–258 (2010). https://doi.org/10.1152/physrev.00015.2009

    Article  Google Scholar 

  3. Hue, L., Taegtmeyer, H.: The Randle cycle revisited: a new head for an old hat. Am. J. Physiol. Metab. 297, E578 (2009). https://doi.org/10.1152/ajpendo.00093.2009

    Article  Google Scholar 

  4. Neubauer, S.: The failing heart—an engine out of fuel. N. Engl. J. Med. 356, 1140 (2007)

    Article  Google Scholar 

  5. Brown, T.R., Kincaid, B.M., Ugurbil, K.: NMR chemical shift imaging in three dimensions. Proc. Natl. Acad. Sci. U. S. A. 79, 3523 (1982). https://doi.org/10.1073/pnas.79.11.3523

    Article  Google Scholar 

  6. Golman, K., Petersson, J.S., Magnusson, P., Johansson, E., Åkeson, P., Chai, C.M., Hansson, G., Månsson, S.: Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI. Magn. Reson. Med. 59, 1005 (2008). https://doi.org/10.1002/mrm.21460

    Article  Google Scholar 

  7. Cunningham, C.H., Chen, A.P., Albers, M.J., Kurhanewicz, J., Hurd, R.E., Yen, Y.F., Pauly, J.M., Nelson, S.J., Vigneron, D.B.: Double spin-echo sequence for rapid spectroscopic imaging of hyperpolarized 13C. J. Magn. Reson. 187, 357 (2007). https://doi.org/10.1016/j.jmr.2007.05.014

    Article  Google Scholar 

  8. Lau, A.Z., Chen, A.P., Ghugre, N.R., Ramanan, V., Lam, W.W., Connelly, K.A., Wright, G.A., Cunningham, C.H.: Rapid multislice imaging of hyperpolarized 13C pyruvate and bicarbonate in the heart. Magn. Reson. Med. 64, 1323 (2010). https://doi.org/10.1002/mrm.22525

    Article  Google Scholar 

  9. Wiesinger, F., Weidl, E., Menzel, M.I., Janich, M.A., Khegai, O., Glaser, S.J., Haase, A., Schwaiger, M., Schulte, R.F.: IDEAL spiral CSI for dynamic metabolic MR imaging of hyperpolarized [1-13C]pyruvate. Magn. Reson. Med. 68, 8 (2012). https://doi.org/10.1002/mrm.23212

    Article  Google Scholar 

  10. Lau, A.Z., Chen, A.P., Hurd, R.E., Cunningham, C.H.: Spectral-spatial excitation for rapid imaging of DNP compounds. NMR Biomed. 24, 988 (2011). https://doi.org/10.1002/nbm.1743

    Article  Google Scholar 

  11. Schroeder, M.A., Atherton, H.J., Ball, D.R., Cole, M.A., Heather, L.C., Griffin, J.L., Clarke, K., Radda, G.K., Tyler, D.J.: Real-time assessment of Krebs cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy. FASEB J. 23, 2529 (2009). https://doi.org/10.1096/fj.09-129171

    Article  Google Scholar 

  12. Schroeder, M.A., Atherton, H.J., Dodd, M.S., Lee, P., Cochlin, L.E., Radda, G.K., Clarke, K., Tyler, D.J.: The cycling of acetyl-coenzyme a through acetylcarnitine buffers cardiac substrate supply: a hyperpolarized 13C magnetic resonance study. Circ. Cardiovasc. Imaging. 5, 201 (2012). https://doi.org/10.1161/CIRCIMAGING.111.969451

    Article  Google Scholar 

  13. Chen, A.P., Hurd, R.E., Schroeder, M.A., Lau, A.Z., Gu, Y.P., Lam, W.W., Barry, J., Tropp, J., Cunningham, C.H.: Simultaneous investigation of cardiac pyruvate dehydrogenase flux, Krebs cycle metabolism and pH, using hyperpolarized [1,2-13C 2]pyruvate in vivo. NMR Biomed. 25, 305–311 (2012). https://doi.org/10.1002/nbm.1749

    Article  Google Scholar 

  14. Timm, K.N., Miller, J.J., Henry, J.A., Tyler, D.J.: Cardiac applications of hyperpolarised magnetic resonance. Prog. Nucl. Magn. Reson. Spectrosc. 106–107, 66 (2018). https://doi.org/10.1016/j.pnmrs.2018.05.002

    Article  Google Scholar 

  15. Chen, A.P., Lau, J.Y.C., Alvares, R.D.A., Cunningham, C.H.: Using [1-13C]lactic acid for hyperpolarized 13C MR cardiac studies. Magn. Reson. Med. 73, 2087–2093 (2015). https://doi.org/10.1002/mrm.25354

    Article  Google Scholar 

  16. Koellisch, U., Gringeri, C.V., Rancan, G., Farell, E.V., Menzel, M.I., Haase, A., Schwaiger, M., Schulte, R.F.: Metabolic imaging of hyperpolarized [1-13C]acetate and [1-13C]acetylcarnitine—investigation of the influence of dobutamine induced stress. Magn. Reson. Med. 74, 1011–1018 (2015). https://doi.org/10.1002/mrm.25485

    Article  Google Scholar 

  17. Bastiaansen, J.A.M., Cheng, T., Lei, H., Gruetter, R., Comment, A.: Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance. J. Mol. Cell. Cardiol. 87, 129–137 (2015). https://doi.org/10.1016/j.yjmcc.2015.08.012

    Article  Google Scholar 

  18. Abdurrachim, D., Woo, C.C., Teo, X.Q., Chan, W.X., Radda, G.K., Lee, P.T.H.: A new hyperpolarized 13 C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart. Sci. Rep. 9, 5532 (2019). https://doi.org/10.1038/s41598-019-39378-w

    Article  Google Scholar 

  19. Miller, J.J., Ball, D.R., Lau, A.Z., Tyler, D.J.: Hyperpolarized ketone body metabolism in the rat heart. NMR Biomed. 31, e3912 (2018). https://doi.org/10.1002/nbm.3912

    Article  Google Scholar 

  20. Ball, D.R., Rowlands, B., Dodd, M.S., Le Page, L., Ball, V., Carr, C.A., Clarke, K., Tyler, D.J.: Hyperpolarized butyrate: a metabolic probe of short chain fatty acid metabolism in the heart. Magn. Reson. Med. 71, 1663 (2014). https://doi.org/10.1002/mrm.24849

    Article  Google Scholar 

  21. Bastiaansen, J.A.M., Merritt, M.E., Comment, A.: Measuring changes in substrate utilization in the myocardium in response to fasting using hyperpolarized [1-13C]butyrate and [1-13C]pyruvate. Sci. Rep. 6, 25573 (2016). https://doi.org/10.1038/srep25573

    Article  Google Scholar 

  22. Latipää, P.M., Peuhkurinen, K.J., Hiltunen, J.K., Hassinen, I.E.: Regulation of pyruvate dehydrogenase during infusion of fatty acids of varying chain lengths in the perfused rat heart. J. Mol. Cell. Cardiol. 17, 1161 (1985). https://doi.org/10.1016/S0022-2828(85)80112-7

    Article  Google Scholar 

  23. Sherry, A.D., Malloy, C.R., Roby, R.E., Rajagopal, A., Jeffrey, F.M.H.: Propionate metabolism in the rat heart by 13C n. m.r. spectroscopy. Biochem. J. 254(2), 593–598 (1988). https://doi.org/10.1042/bj2540593

    Article  Google Scholar 

  24. Merritt, M.E., Harrison, C., Storey, C., Jeffrey, F.M., Sherry, A.D., Malloy, C.R.: Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR. Proc. Natl. Acad. Sci. U. S. A. 104, 19773–19777 (2007). https://doi.org/10.1073/pnas.0706235104

    Article  Google Scholar 

  25. Khemtong, C., Carpenter, N.R., Lumata, L.L., Merritt, M.E., Moreno, K.X., Kovacs, Z., Malloy, C.R., Sherry, A.D.: Hyperpolarized 13C NMR detects rapid drug-induced changes in cardiac metabolism. Magn. Reson. Med. 74, 312 (2015). https://doi.org/10.1002/mrm.25419

    Article  Google Scholar 

  26. Schroeder, M.A., Cochlin, L.E., Heather, L.C., Clarke, K., Radda, G.K., Tyler, D.J.: In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc. Natl. Acad. Sci. 105, 12051–12056 (2008). https://doi.org/10.1073/pnas.0805953105

    Article  Google Scholar 

  27. Atherton, H.J., Schroeder, M.A., Dodd, M.S., Heather, L.C., Carter, E.E., Cochlin, L.E., Nagel, S., Sibson, N.R., Radda, G.K., Clarke, K., Tyler, D.J.: Validation of the in vivo assessment of pyruvate dehydrogenase activity using hyperpolarised 13C MRS. NMR Biomed. 24, 201 (2011). https://doi.org/10.1002/nbm.1573

    Article  Google Scholar 

  28. Dodd, M.S., Ball, V., Bray, R., Ashrafian, H., Watkins, H., Clarke, K., Tyler, D.J.: In vivo mouse cardiac hyperpolarized magnetic resonance spectroscopy. J. Cardiovasc. Magn. Reson. 15, 19 (2013). https://doi.org/10.1186/1532-429X-15-19

    Article  Google Scholar 

  29. Menichetti, L., Frijia, F., Flori, A., Wiesinger, F., Lionetti, V., Giovannetti, G., Aquaro, G.D., Recchia, F.A., Ardenkjaer-Larsen, J.H., Santarelli, M.F., Lombardi, M.: Assessment of real-time myocardial uptake and enzymatic conversion of hyperpolarized [1-13C]pyruvate in pigs using slice selective magnetic resonance spectroscopy. Contrast Media Mol. Imaging. 7, 85 (2012). https://doi.org/10.1002/cmmi.480

    Article  Google Scholar 

  30. Chen, A.P., Lau, A.Z., Gu, Y.P., Schroeder, M.A., Barry, J., Cunningham, C.H.: Probing the cardiac malate–aspartate shuttle non-invasively using hyperpolarized [1,2-13C2]pyruvate. NMR Biomed. 31, e3845 (2018). https://doi.org/10.1002/nbm.3845

    Article  Google Scholar 

  31. Lau, A.Z., Chen, A.P., Barry, J., Graham, J.J., Dominguez-Viqueira, W., Ghugre, N.R., Wright, G.A., Cunningham, C.H.: Reproducibility study for free-breathing measurements of pyruvate metabolism using hyperpolarized 13C in the heart. Magn. Reson. Med. 69, 1063 (2013). https://doi.org/10.1002/mrm.24342

    Article  Google Scholar 

  32. Hansen, E.S.S., Tougaard, R.S., Nørlinger, T.S., Mikkelsen, E., Nielsen, P.M., Bertelsen, L.B., Bøtker, H.E., Jørgensen, H.S., Laustsen, C.: Imaging porcine cardiac substrate selection modulations by glucose, insulin and potassium intervention: a hyperpolarized [1-13C]pyruvate study. NMR Biomed. 30 (2017). https://doi.org/10.1002/nbm.3702

  33. Miller, J.J., Lau, A.Z., Teh, I., Schneider, J.E., Kinchesh, P., Smar, T.S., Ball, V., Sibson, N.R., Tyler, D.J.: Robust and high resolution hyperpolarized metabolic imaging of the rat heart at 7 t with 3d spectral-spatial EPI. Magn. Reson. Med. 75(4), 1515–1524 (2016). https://doi.org/10.1002/mrm.25730

    Article  Google Scholar 

  34. Sigfridsson, A., Weiss, K., Wissmann, L., Busch, J., Krajewski, M., Batel, M., Batsios, G., Ernst, M., Kozerke, S.: Hybrid multiband excitation multiecho acquisition for hyperpolarized 13C spectroscopic imaging. Magn. Reson. Med. 73, 1713 (2015). https://doi.org/10.1002/mrm.25294

    Article  Google Scholar 

  35. Weiss, K., Sigfridsson, A., Wissmann, L., Busch, J., Batel, M., Krajewski, M., Ernst, M., Kozerke, S.: Accelerating hyperpolarized metabolic imaging of the heart by exploiting spatiotemporal correlations. NMR Biomed. 26, 1380 (2013). https://doi.org/10.1002/nbm.2963

    Article  Google Scholar 

  36. Olsson, L.E., Chai, C.M., Axelsson, O., Karlsson, M., Golman, K., Petersson, J.S.: MR coronary angiography in pigs with intraarterial injections of a hyperpolarized 13C substance. Magn. Reson. Med. 55, 731 (2006). https://doi.org/10.1002/mrm.20847

    Article  Google Scholar 

  37. Fuetterer, M., Busch, J., Peereboom, S.M., Von Deuster, C., Wissmann, L., Lipiski, M., Fleischmann, T., Cesarovic, N., Stoeck, C.T., Kozerke, S.: Hyperpolarized 13C urea myocardial first-pass perfusion imaging using velocity-selective excitation. J. Cardiovasc. Magn. Reson. 19, 46 (2017). https://doi.org/10.1186/s12968-017-0364-4

    Article  Google Scholar 

  38. Lau, A.Z., Miller, J.J., Robson, M.D., Tyler, D.J.: Cardiac perfusion imaging using hyperpolarized 13c urea using flow sensitizing gradients. Magn. Reson. Med. 75, 1474 (2016). https://doi.org/10.1002/mrm.25713

    Article  Google Scholar 

  39. Fuetterer, M., Busch, J., Traechtler, J., Wespi, P., Peereboom, S.M., Sauer, M., Lipiski, M., Fleischmann, T., Cesarovic, N., Stoeck, C.T., Kozerke, S.: Quantitative myocardial first-pass cardiovascular magnetic resonance perfusion imaging using hyperpolarized [1-13 C] pyruvate. J. Cardiovasc. Magn. Reson. 20, 73 (2018). https://doi.org/10.1186/s12968-018-0495-2

    Article  Google Scholar 

  40. Lau, A.Z., Miller, J.J., Robson, M.D., Tyler, D.J.: Simultaneous assessment of cardiac metabolism and perfusion using copolarized [1-13C]pyruvate and 13C-urea. Magn. Reson. Med. 77, 151 (2017). https://doi.org/10.1002/mrm.26106

    Article  Google Scholar 

  41. Williamson, D.H., Lund, P., Krebs, H.A.: The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem. J. 103, 514 (1967). https://doi.org/10.1042/bj1030514

    Article  Google Scholar 

  42. Lewis, A.J.M., Miller, J.J.J., McCallum, C., Rider, O.J., Neubauer, S., Heather, L.C., Tyler, D.J.: Assessment of metformin-induced changes in cardiac and hepatic redox state using hyperpolarized [1-13C]pyruvate. Diabetes. 65, 3544 (2016). https://doi.org/10.2337/db16-0804

    Article  Google Scholar 

  43. Chen, W., Sharma, G., Jiang, W., Maptue, N.R., Malloy, C.R., Sherry, A.D., Khemtong, C.: Metabolism of hyperpolarized 13C-acetoacetate to β-hydroxybutyrate detects real-time mitochondrial redox state and dysfunction in heart tissue. NMR Biomed. 32, e4091 (2019). https://doi.org/10.1002/nbm.4091

    Article  Google Scholar 

  44. Gallagher, F.A., Kettunen, M.I., Day, S.E., Hu, D.E., Rdenkjaer-Larsen, J.H., in’t Zandt, R., Jensen, P.R., Karlsson, M., Golman, K., Lerche, M.H., Brindle, K.M.: Magnetic resonance imaging of pH in vivo using hyperpolarized C-13-labelled bicarbonate. Nature. 453, 940-U73 (2008)

    Article  Google Scholar 

  45. Schroeder, M.A., Swietach, P., Atherton, H.J., Gallagher, F.A., Lee, P., Radda, G.K., Clarke, K., Tyler, D.J.: Measuring intracellular pH in the heart using hyperpolarized carbon dioxide and bicarbonate: a 13C and 31P magnetic resonance spectroscopy study. Cardiovasc. Res. 86, 82–91 (2010). https://doi.org/10.1093/cvr/cvp396

    Article  Google Scholar 

  46. Lau, A.Z., Miller, J.J., Tyler, D.J.: Mapping of intracellular pH in the in vivo rodent heart using hyperpolarized [1-13C]pyruvate. Magn. Reson. Med. 77, 1810–1817 (2017). https://doi.org/10.1002/mrm.26260

    Article  Google Scholar 

  47. Mansor, L.S., Gonzalez, E.R., Cole, M.A., Tyler, D.J., Beeson, J.H., Clarke, K., Carr, C.A., Heather, L.C.: Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin. Cardiovasc. Diabetol. 12, 136 (2013). https://doi.org/10.1186/1475-2840-12-136

    Article  Google Scholar 

  48. Le Page, L.M., Rider, O.J., Lewis, A.J., Ball, V., Clarke, K., Johansson, E., Carr, C.A., Heather, L.C., Tyler, D.J.: Increasing pyruvate dehydrogenase flux as a treatment for diabetic cardiomyopathy: a combined 13C hyperpolarized magnetic resonance and echocardiography study. Diabetes. 64, 2735–2743 (2015). https://doi.org/10.2337/db14-1560

    Article  Google Scholar 

  49. Heather, L.C., Pates, K.M., Atherton, H.J., Cole, M.A., Ball, D.R., Evans, R.D., Glatz, J.F., Luiken, J.J., Griffin, J.L., Clarke, K.: Differential translocation of the fatty acid transporter, FAT/CD36, and the glucose transporter, GLUT4, coordinates changes in cardiac substrate metabolism during ischemia and reperfusion. Circ. Heart Fail. 6, 1058–1066 (2013). https://doi.org/10.1161/CIRCHEARTFAILURE.112.000342

    Article  Google Scholar 

  50. Merritt, M.E., Harrison, C., Storey, C., Sherry, A.D., Malloy, C.R.: Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized 13CO2 and H13CO3. Magn. Reson. Med. 60, 1029–1036 (2008). https://doi.org/10.1002/mrm.21760

    Article  Google Scholar 

  51. Oh-Ici, D., Wespi, P., Busch, J., Wissmann, L., Krajewski, M., Weiss, K., Sigfridsson, A., Messroghli, D., Kozerke, S.: Hyperpolarized metabolic MR imaging of acute myocardial changes and recovery after ischemia-reperfusion in a small-animal model. Radiology. 278, 742–751 (2016). https://doi.org/10.1148/radiol.2015151332

    Article  Google Scholar 

  52. Shaw, L.J., Berman, D.S., Maron, D.J., Mancini, G.B.J., Hayes, S.W., Hartigan, P.M., Weintraub, W.S., O’Rourke, R.A., Dada, M., Spertus, J.A., Chaitman, B.R., Friedman, J., Slomka, P., Heller, G.V., Germano, G., Gosselin, G., Berger, P., Kostuk, W.J., Schwartz, R.G., Knudtson, M., Veledar, E., Bates, E.R., McCallister, B., Teo, K.K., Boden, W.E.: Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 117, 1283–1291 (2008). https://doi.org/10.1161/CIRCULATIONAHA.107.743963

    Article  Google Scholar 

  53. Ball, D.R., Cruickshank, R., Carr, C.A., Stuckey, D.J., Lee, P., Clarke, K., Tyler, D.J.: Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1-13C]pyruvate. NMR Biomed. 26, 1441–1450 (2013). https://doi.org/10.1002/nbm.2972

    Article  Google Scholar 

  54. Lauritzen, M.H., Magnusson, P., Laustsen, C., Butt, S.A., Ardenkjær-Larsen, J.H., Sogaard, L.V., Paulson, O.B., Akeson, P.: Imaging regional metabolic changes in the ischemic rat heart in vivo using hyperpolarized [1-13 C]pyruvate. Tomography. 3, 123 (2017). https://doi.org/10.18383/j.tom.2017.00008

    Article  Google Scholar 

  55. Lewis, A.J., Miller, J.J., Lau, A.Z., Curtis, M.K., Rider, O.J., Choudhury, R.P., Neubauer, S., Cunningham, C.H., Carr, C.A., Tyler, D.J.: Non-invasive immuno-metabolic cardiac inflammation imaging using hyperpolarized magnetic resonance. Circ. Res. 122(8), 1084–1093 (2018). https://doi.org/10.1161/CIRCRESAHA.117.312535

    Article  Google Scholar 

  56. Miller, J.J., Lau, A.Z., Nielsen, P.M., McMullen-Klein, G., Lewis, A.J., Jespersen, N.R., Ball, V., Gallagher, F.A., Carr, C.A., Laustsen, C., Bøtker, H.E., Tyler, D.J., Schroeder, M.A.: Hyperpolarized [1,4-13C2]fumarate enables magnetic resonance-based imaging of myocardial necrosis. JACC Cardiovasc. Imaging. 11(11), 1594–1606 (2018)

    Article  Google Scholar 

  57. Gallagher, F.A., Kettunen, M.I., Hu, D.-E., Jensen, P.R., Zandt, R., Karlsson, M., Gisselsson, A., Nelson, S.K., Witney, T.H., Bohndiek, S.E., Hansson, G., Peitersen, T., Lerche, M.H., Brindle, K.M.: Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors. Proc. Natl. Acad. Sci. 106, 19801–19806 (2009). https://doi.org/10.1073/pnas.0911447106

    Article  Google Scholar 

  58. Dodd, M.S., Ball, D.R., Schroeder, M.A., Le Page, L.M., Atherton, H.J., Heather, L.C., Seymour, A.M., Ashrafian, H., Watkins, H., Clarke, K., Tyler, D.J.: In vivo alterations in cardiac metabolism and function in the spontaneously hypertensive rat heart. Cardiovasc. Res. 95, 69–76 (2012). https://doi.org/10.1093/cvr/cvs164

    Article  Google Scholar 

  59. Seymour, A.-M.L., Giles, L., Ball, V., Miller, J.J., Clarke, K., Carr, C.A., Tyler, D.J.: In vivo assessment of cardiac metabolism and function in the abdominal aortic banding model of compensated cardiac hypertrophy. Cardiovasc. Res. 106, 249–260 (2015). https://doi.org/10.1093/cvr/cvv101

    Article  Google Scholar 

  60. Siehl, D., Chua, B.H.L., Lautensack-Belser, N., Morgan, H.E.: Faster protein and ribosome synthesis in thyroxine-induced hypertrophy of rat heart. Am. J. Phys. Cell Phys. 248, C309 (1985). https://doi.org/10.1152/ajpcell.1985.248.3.c309

    Article  Google Scholar 

  61. Orfali, K.A., Fryer, L.G.D., Holness, M.J., Sugden, M.C.: Interactive effects of insulin and triiodothyronine on pyruvate dehydrogenase kinase activity in cardiac myocytes. J. Mol. Cell. Cardiol. 27, 901 (1995). https://doi.org/10.1016/0022-2828(95)90040-3

    Article  Google Scholar 

  62. Atherton, H.J., Dodd, M.S., Heather, L.C., Schroeder, M.A., Griffin, J.L., Radda, G.K., Clarke, K., Tyler, D.J.: Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study. Circulation. 123, 2552–2561 (2011). https://doi.org/10.1161/CIRCULATIONAHA.110.011387

    Article  Google Scholar 

  63. Dodd, M.S., Atherton, H.J., Carr, C.A., Stuckey, D.J., West, J.A., Griffin, J.L., Radda, G.K., Clarke, K., Heather, L.C., Tyler, D.J.: Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. Circ. Cardiovasc. Imaging. 7, 895–904 (2014). https://doi.org/10.1161/CIRCIMAGING.114.001857

    Article  Google Scholar 

  64. Schroeder, M.A., Lau, A.Z., Chen, A.P., Gu, Y., Nagendran, J., Barry, J., Hu, X., Dyck, J.R.B., Tyler, D.J., Clarke, K., Connelly, K.A., Wright, G.A., Cunningham, C.H.: Hyperpolarized 13C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart. Eur. J. Heart Fail. 15, 130–140 (2013). https://doi.org/10.1093/eurjhf/hfs192

    Article  Google Scholar 

  65. Bakermans, A.J., Dodd, M.S., Nicolay, K., Prompers, J.J., Tyler, D.J., Houten, S.M.: Myocardial energy shortage and unmet anaplerotic needs in the fasted long-chain acyl-co a dehydrogenase knockout mouse. Cardiovasc. Res. 100, 441 (2013). https://doi.org/10.1093/cvr/cvt212

    Article  Google Scholar 

  66. Slingo, M., Cole, M., Carr, C., Curtis, M., Dodd, M., Giles, L., Heather, L., Tyler, D., Clarke, K., Robbins, P.A.: The von hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism. Am. J. Physiol. Heart Circ. Physiol. 311, H759 (2016). https://doi.org/10.1152/ajpheart.00912.2015

    Article  Google Scholar 

  67. Betts, C.A., McClorey, G., Healicon, R., Hammond, S.M., Manzano, R., Muses, S., Ball, V., Godfrey, C., Merritt, T.M., Van Westering, T., O’Donovan, L., Wells, K.E., Gait, M.J., Wells, D.J., Tyler, D., Wood, M.J.: Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment. Hum. Mol. Genet. 28(3), 396–406 (2019). https://doi.org/10.1093/hmg/ddy346

    Article  Google Scholar 

  68. Rohm, M., Savic, D., Ball, V., Curtis, M.K., Bonham, S., Fischer, R., Legrave, N., MacRae, J.I., Tyler, D.J., Ashcroft, F.M.: Cardiac dysfunction and metabolic inflexibility in a mouse model of diabetes without dyslipidemia. Diabetes. 67, 1057 (2018). https://doi.org/10.2337/db17-1195

    Article  Google Scholar 

  69. Lee, S.S., Pineau, T., Drago, J., Lee, E.J., Owens, J.W., Kroetz, D.L., Fernandez-Salguero, P.M., Westphal, H., Gonzalez, F.J.: Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol. 15, 3012 (1995). https://doi.org/10.1128/mcb.15.6.3012

    Article  Google Scholar 

  70. Djouadi, F., Weinheimer, C.J., Saffitz, J.E., Pitchford, C., Bastin, J., Gonzalez, F.J., Kelly, D.P.: A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor α-deficient mice. J. Clin. Invest. 102, 1083 (1998). https://doi.org/10.1172/JCI3949

    Article  Google Scholar 

  71. Schroeder, M.A., Clarke, K., Neubauer, S., Tyler, D.J.: Hyperpolarized magnetic resonance: a novel technique for the in vivo assessment of cardiovascular disease. Circulation. 124, 1580 (2011). https://doi.org/10.1161/CIRCULATIONAHA.111.024919

    Article  Google Scholar 

  72. Rider, O.J., Tyler, D.J.: Clinical implications of cardiac hyperpolarized magnetic resonance imaging. J. Cardiovasc. Magn. Reson. 15(1), 93 (2013)

    Article  Google Scholar 

  73. Nelson, S.J., Kurhanewicz, J., Vigneron, D.B., Larson, P.E.Z., Harzstark, A.L., Ferrone, M., Van Criekinge, M., Chang, J.W., Bok, R., Park, I., Reed, G., Carvajal, L., Small, E.J., Munster, P., Weinberg, V.K., Ardenkjaer-Larsen, J.H., Chen, A.P., Hurd, R.E., Odegardstuen, L.I., Robb, F.J., Tropp, J., Murray, J.A.: Metabolic imaging of patients with prostate cancer using hyperpolarized [1–13C]pyruvate. Sci. Transl. Med. 5, 198ra108 (2013)

    Article  Google Scholar 

  74. Rider, O.J., Apps, A., Miller, J.J., Lau, J.Y., Lewis, A.J., Peterzan, M.A., Dodd, M.S., Lau, A.Z., Trumper, C., Gallagher, F., Grist, J.T., Brindle, K., Neubauer, S., Tyler, D.J.: Non-invasive in vivo assessment of cardiac metabolism in the healthy and diabetic human heart using hyperpolarized 13 C MRI. Circ. Res. 126, 725 (2020). https://doi.org/10.1161/CIRCRESAHA.119.316260

    Article  Google Scholar 

  75. Cunningham, C.H., Lau, J.Y.C., Chen, A.P., Geraghty, B.J., Perks, W.J., Roifman, I., Wright, G.A., Connelly, K.A.: Hyperpolarized 13C metabolic MRI of the human heart: initial experience. Circ. Res. 119, 1177 (2016). https://doi.org/10.1161/CIRCRESAHA.116.309769

    Article  Google Scholar 

Further Reading

  • Cunningham, C.H., Lau, J.Y.C., Chen, A.P., Geraghty, B.J., Perks, W.J., Roifman, I., Wright, G.A., Connelly, K.A.: Hyperpolarized 13C metabolic MRI of the human heart: initial experience. Circ. Res. 119, 1177 (2016). https://doi.org/10.1161/CIRCRESAHA.116.309769

    Article  Google Scholar 

  • Fuetterer, M., Busch, J., Traechtler, J., Wespi, P., Peereboom, S.M., Sauer, M., Lipiski, M., Fleischmann, T., Cesarovic, N., Stoeck, C.T., Kozerke, S.: Quantitative myocardial first-pass cardiovascular magnetic resonance perfusion imaging using hyperpolarized [1-13 C] pyruvate. J. Cardiovasc. Magn. Reson. 20, 73 (2018). https://doi.org/10.1186/s12968-018-0495-2

    Article  Google Scholar 

  • Ingwall: ATP and the heart. Kluwer Academic, Boston (2002)

    Book  Google Scholar 

  • Lewis, A.J., Miller, J.J., Lau, A.Z., Curtis, M.K., Rider, O.J., Choudhury, R.P., Neubauer, S., Cunningham, C.H., Carr, C.A., Tyler, D.J.: Non-invasive immuno-metabolic cardiac inflammation imaging using hyperpolarized magnetic resonance. Circ. Res. 122(8), 1084–1093 (2018). https://doi.org/10.1161/CIRCRESAHA.117.312535

    Article  Google Scholar 

  • Rider, O.J., Apps, A., Miller, J.J., Lau, J.Y., Lewis, A.J., Peterzan, M.A., Dodd, M.S., Lau, A.Z., Trumper, C., Gallagher, F., Grist, J.T., Brindle, K., Neubauer, S., Tyler, D.J.: Non-invasive in vivo assessment of cardiac metabolism in the healthy and diabetic human heart using hyperpolarized 13C MRI. Circ. Res. 126, 725 (2020). https://doi.org/10.1161/CIRCRESAHA.119.316260

    Article  Google Scholar 

  • Schroeder, M.A., Cochlin, L.E., Heather, L.C., Clarke, K., Radda, G.K., Tyler, D.J.: In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc. Natl. Acad. Sci. 105, 12051–12056 (2008). https://doi.org/10.1073/pnas.0805953105

    Article  Google Scholar 

Download references

Acknowledgments

The authors would also like to acknowledge financial support provided by the British Heart Foundation (BHF) in the form of a BHF Immediate Research Fellowship and BHF Senior Research Fellowships respectively (KT: FS/16/7/31843, DJT: FS/14/17/30634 and FS/19/18/34252). All authors would also like to acknowledge the support provided by the OXFORD-BHF Centre for Research Excellence (grant no. RE/13/1/30181) and the National Institute for Health Research Oxford Biomedical Research Centre programme.

Author information

Authors and Affiliations

  1. Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, UK

    Angus Lau, Kerstin Timm & Damian Tyler

  2. Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, UK

    Angus Lau & Damian Tyler

Authors
  1. Angus Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kerstin Timm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Damian Tyler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Damian Tyler .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, USA

    Thomas Jue

  2. Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, Baltimore, MD, USA

    Dirk Mayer

Problems

Problems

  1. 1.

    At a normal physiological intracellular pH of 7.2 and assuming a pKa of 6.17 [44] for the carbonic anhydrase reaction, what is the expected ratio of hyperpolarized bicarbonate and CO2 that you would expect to see following injection of hyperpolarized [1-13C]pyruvate?

  2. 2.

    What are the challenges faced when trying to use hyperpolarized agents to assess perfusion in the in vivo heart?

  3. 3.

    Why does care need to be taken when interpreting the results of hyperpolarized [2-13C]pyruvate data in relation to incorporation of the 13C label into the TCA cycle in situations where PDH flux is impaired (e.g. in the diabetic heart)?

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lau, A., Timm, K., Tyler, D. (2021). Novel Views on Heart Function from Dynamic Hyperpolarized NMR. In: Jue, T., Mayer, D. (eds) Dynamic Hyperpolarized Nuclear Magnetic Resonance. Handbook of Modern Biophysics. Springer, Cham. https://doi.org/10.1007/978-3-030-55043-1_9

Download citation

Publish with us

Policies and ethics

Search

Navigation